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Molecular Features of the YAP Inhibitor Verteporfin: Synthesis of Hexasubstituted Dipyrrins as Potential Inhibitors of YAP/TAZ, the Downstream Effectors of the Hippo Pathway
Author(s) -
Gibault Floriane,
Bailly Fabrice,
Corvaisier Matthieu,
Coevoet Mathilde,
Huet Guillemette,
Melnyk Patricia,
Cotelle Philippe
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700063
Subject(s) - chemistry , photosensitizer , verteporfin , photodynamic therapy , porphyrin , hippo signaling pathway , effector , kinase , stereochemistry , cancer research , biochemistry , biology , photochemistry , retinal , organic chemistry , choroidal neovascularization
Porphyrin derivatives, in particular verteporfin (VP), a photosensitizer initially designed for cancer therapy, have been identified as inhibitors of the YAP–TEAD interaction and transcriptional activity. Herein we report the efficient convergent synthesis of the dipyrrin half of protoporphyrin IX dimethyl ester (PPIX‐DME), in which the sensitive vinyl group was created at the final stage by a dehydroiodination reaction. Two other dipyrrin derivatives were synthesized, including dipyrrin 19 [( Z )‐2‐((3,5‐dimethyl‐4‐vinyl‐2 H ‐pyrrol‐2‐ylidene)methyl)‐3,5‐dimethyl‐4‐vinyl‐1 H ‐pyrrole], containing two vinyl groups. We found that VP and dipyrrin 19 showed significant inhibitory effects on TEAD transcriptional activity in MDA‐MB‐231 human breast cancer cells, whereas other compounds did not show significant changes. In addition, we observed a marked decrease in both YAP and TAZ levels following VP treatment, whereas dipyrrin 19 treatment primarily decreased the levels of YAP and receptor kinase AXL, a downstream target of YAP. Together, our data suggest that, due to their chemical structures, porphyrin‐ and dipyrrin‐related derivatives can directly target YAP and/or TAZ proteins and inhibit TEAD transcriptional activity.